The present invention is concerned with a process for synthesizing intermediates for compounds which inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular certain oligopeptide analogs, such as Compound J (i.e., indinavir) and other compounds as described in U.S. Pat. No. 5,413,999. These compounds are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). These compounds are also useful for inhibiting renin and other proteases.
1(S)-Amino-2(R)-hydroxy indan of the structure ##STR1##
is used to form an amide sidechain group on Compound J, a potent inhibitor of HIV protease, via methods described in U.S. Pat. No. 5,413,999 and in Merck 19464IA, U.S. Ser. No. 08/696,667, filed Aug. 14, 1996, both of which are incorporated herein by reference in their entireties.
Previous attempts at synthesis involve inefficient production of the racemate 1(+/-)amino-2(+/-) hydroxy indan from the racemic indene oxide. Other attempts at synthesis involve bioconversion of indene with a fungal haloperoxidase to give predominantly trans-(2S,1S)-bromoindanol, which is then subjected to various chemical steps to give (1S)-amino-(2R)-indanol. Still other attempts at synthesis relate to chemical synthesis with racemic epoxidation of indene as an intermediate step, followed by resolution with L-tartaric acid. Indene epoxide with a high enantiomeric excess can be obtained from indene via Jacobson's S,S-salen manganese catalyst (Jacobsen et al., J. Am. Chem. Soc., vol. 113, 7063-7064 (1991)), but upon hydroxylation to open the epoxide ring only a trans-diol is produced.
The chemical synthesis of cis-indanediols via the asymmetric oxidation of indene has been reported, but only in low enantiomeric excess. Tomoka et al., Chem. Pharm. Bull., vol. 38, 2133-2135 (1990), for example, discloses the formation of 1S,2R-indanediol in 30% enantiomeric excess via oxidation of indene using a stoichiometric amount of an osmium tetroxide-chiral amine complex at -78.degree. C. Resolution of the indanediol product would be required in order to prepare an enantiomeric derivative such as ((S)-amino-(2R)-indanol.
U.S. Ser. No. 08/696,667 discloses an improved synthetic method in which the tartaric acid resolution step is eliminated. The method of U.S. Ser. No. 08/696,667 involves the stereoselective bioconversion of indene to cis-(1S,2R)-indanediol by the action of the enzyme dioxygenase, followed by further chemical treatment of the indanediol (e.g., treatment with a nitrite in the presence of acid in accordance with the Ritter reaction) to give (1S)-amino-(2R)-indanol. Preferred sources for the enzyme dioxygenase disclosed in U.S. Ser. No. 08/696,667 include Pseudomonas putida 421-5 (ATCC 55687) and Rhodococcus B264-1 (ATCC 55806).
While the route disclosed in USSN 08/696,667 constitutes a practical means for the production of a cis-(1S,2R)-indanediol intermediate, other indene metabolites such as indanone, indenol and keto-hydroxy compounds can form as by-products, which can both limit the yield and complicate the recovery of the desired indanediol product. The maximum isolated yield of cis-(1S,2R)-indanediol in the 08/696,667 process is typically no more than about 20%, which in turn limits the potential yield of the (1S)-amino-(2R)-indanol derivative. There exists the need for bioconversion processes which produce cis-(1S,2R)-indanediol from indene in higher yields and with little or no by-product formation.